CN113402444B - Carbazole compound and application thereof in preparation of medicines for treating fatty liver and type 2 diabetes and other metabolic related diseases - Google Patents

Carbazole compound and application thereof in preparation of medicines for treating fatty liver and type 2 diabetes and other metabolic related diseases Download PDF

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CN113402444B
CN113402444B CN202110673887.0A CN202110673887A CN113402444B CN 113402444 B CN113402444 B CN 113402444B CN 202110673887 A CN202110673887 A CN 202110673887A CN 113402444 B CN113402444 B CN 113402444B
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carbazole compound
fatty liver
diabetes
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李珊
秦志平
刘薇
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Shanghai Oukun Biomedical Technology Co ltd
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Abstract

The invention relates to a carbazole compound and application thereof in preparing medicines for treating fatty liver, type 2 diabetes and other metabolic related diseases, wherein the carbazole compound has a structural general formula shown in formula (I), wherein R 1 is selected from halogen, hydroxy or C 1-C6 alkoxy; each of R 2 and R 3 is independently selected from (a) hydrogen or formyl; (b) C 5-C8 heterocyclyl or aryl, optionally substituted with 0-4R 4; wherein R 4 is selected from C 1-C6 alkoxy, C 2-C6 alkenyloxy, C 2-C6 alkynyloxy, or halogen; each of X 1 and X 2 is independently selected from hydrogen or halogen; each of Z 1 and Z 2 is independently selected from hydrogen, cyano or-SOp-R 5; wherein p is selected from 0, 1 or 2; r 5 is selected from the group consisting of C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl; each of n and m is independently selected from 1,2, 3 or 4. The compound of the invention has obviously improved therapeutic effect on glycolipid metabolic diseases.

Description

Carbazole compound and application thereof in preparation of medicines for treating fatty liver and type 2 diabetes and other metabolic related diseases
Technical Field
The invention relates to the field of pharmaceutical compounds, in particular to a carbazole compound and application thereof in preparing medicines for treating fatty liver, type 2 diabetes and other metabolic related diseases.
Background
With the global prevalence of obesity and its metabolic syndrome, metabolic diseases such as obesity, diabetes and fatty liver disease have become important diseases in the rich areas of europe and america and China, and are major health problems. Fatty liver includes simple fatty liver and steatohepatitis. Part of patients with simple fatty liver gradually progress to steatohepatitis, and the liver produces severe inflammation and fibrosis, resulting in liver fibrosis, cirrhosis and even hepatocellular carcinoma. Treatment for fatty liver disease is primarily lifestyle intervention, including weight loss, diet improvement, and exercise. There is no approval by the national food and drug administration (CFDA), us FDA (Food and drug administration), or European medical office EMA (European MEDICINES AGENCY) for the treatment of fatty liver disease. Diabetes is the occurrence of absolute or relative inadequate insulin secretion. The metabolic-related diseases represented by fatty liver and type 2 diabetes have complicated etiology, but they have similar pathogenesis and share many common points.
The patent CN108619137B filed earlier by the inventor discloses application of carbazole compound 3, 6-dibromo-beta-fluoro-N- (3-methoxyphenyl) -9H-carbazole-9-propylamine (P7C 3-A20) in preparation of medicines for treating metabolic diseases and complications thereof, and uses a high-fat high-sugar diet-induced hyperlipidemia, obesity and fatty liver animal model to prove that P7C3-A20 can obviously reduce blood fat and blood sugar, lighten obesity and fatty liver lesions, and uses a myocardial ischemia hypoxia model to simulate ischemic myocardial injury to prove that P7C3-A20 can obviously reduce myocardial cell injury caused by ischemia and hypoxia. The patent provides a new medicine research and development direction for metabolic diseases and complications thereof. Therefore, the P7C3-A20 compound is chemically modified, and the analogue with more obvious research and development effects is of great significance.
Disclosure of Invention
The invention aims at overcoming the defects in the prior art and provides a carbazole compound and pharmaceutically acceptable salts thereof, application and a preparation method thereof.
In a first aspect, the invention provides a carbazole compound, the structural general formula of which is shown in formula (I):
Wherein,
R 1 is selected from halogen, hydroxy or C 1-C6 alkoxy;
each of R 2 and R 3 is independently selected from
(A) Hydrogen or formyl;
(b) C 5-C8 heterocyclyl or aryl, optionally substituted with 0-4R 4; wherein R 4 is selected from C 1-C6 alkoxy, C 2-C6 alkenyloxy, C 2-C6 alkynyloxy, or halogen;
Each of X 1 and X 2 is independently selected from hydrogen or halogen;
each of Z 1 and Z 2 is independently selected from hydrogen, cyano or-SOp-R 5; wherein p is selected from 0,1 or 2; r 5 is selected from the group consisting of C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl;
each of n and m is independently selected from 1, 2, 3 or 4.
As a preferred embodiment of the present invention,
R 1 is selected from halogen or hydroxy;
each of R 2 and R 3 is independently selected from
(A) Hydrogen;
(b) Aryl optionally substituted with 0-4R 4; wherein R 4 is selected from C 1-C6 alkoxy or halogen;
Each of X 1 and X 2 is independently selected from hydrogen or halogen;
Each of Z 1 and Z 2 is independently selected from hydrogen, cyano or-SO 2-R5; wherein R 5 is selected from C 1-C6 alkyl;
each of n and m is independently selected from 1, 2, 3 or 4.
As another preferred embodiment of the present invention,
R 1 is selected from halogen or hydroxy;
R 2 is selected from hydrogen; r 3 is selected from aryl optionally substituted with 0-4R 4, wherein R 4 is selected from C 1-C3 alkoxy;
X 1 is selected from halogen and X 2 is selected from hydrogen;
Z 1 is selected from-SO 2-R5, wherein R 5 is selected from C 1-C3 alkyl; z 2 is selected from hydrogen;
n and m are both 1.
As another preferred embodiment of the present invention,
R 1 is selected from halogen or hydroxy;
R 2 is selected from hydrogen; r 3 is selected from aryl optionally substituted with 0-4R 4, wherein R 4 is selected from C 1-C3 alkoxy;
X 1 is selected from halogen and X 2 is selected from hydrogen;
Z 1 is selected from cyano; z 2 is selected from hydrogen;
n and m are both 1.
As another preferred embodiment of the present invention, the carbazole-based compound is selected from:
1- (3-bromo-6-methanesulfonyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
n- (3- (3-bromo-6-methanesulfonyl-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline;
1- (3-bromo-6-methanesulfonyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
n- (3- (3-bromo-6-cyano-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline;
1- (3-bromo-6-cyano-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol.
In a second aspect, the invention provides pharmaceutically acceptable salts of carbazole-based compounds as described above.
As a preferred embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt.
More preferably, the inorganic acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, or nitric acid; the organic acid comprises acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-toluenesulfonic acid, salicylic acid or oxalic acid.
In a third aspect, the invention provides the use of a carbazole compound or a pharmaceutically acceptable salt of a carbazole compound as described above in the manufacture of a medicament for the treatment of glycolipid metabolic diseases and complications thereof.
In a preferred embodiment of the present invention, the glycolipid metabolic disease and its complications are fatty liver, diabetes, hyperlipidemia, obesity or arteriosclerotic cardiovascular and cerebrovascular diseases.
In a fourth aspect, the present invention provides a method for preparing a carbazole compound as described above:
when the carbazole compound is a carbazole amino alcohol compound, the carbazole amino alcohol compound can be prepared through the following reaction route:
when the carbazole compound is a carbazole fluoroalkyl compound, the carbazole compound can be prepared through the following reaction route:
Herein, the term "C 1-C6 alkoxy" denotes a saturated carbon chain of 1 to 6 carbon atoms in length attached to oxygen, which carbon chain may be linear or branched. For example, "C 1-C6 alkoxy" includes, but is not limited to, methoxy, ethoxy, propoxy, and butoxy.
The term "C 2-C6 alkenyloxy" denotes an unsaturated carbon chain of 2 to 6 carbon atoms in length attached to oxygen, which carbon chain may be linear or branched.
The term "C 2-C6 alkynyloxy" denotes an unsaturated carbon chain of 2 to 6 carbon atoms in length attached to oxygen, which carbon chain may be linear or branched, containing at least one carbon-carbon triple bond.
The term "heterocyclyl" means a 4, 5 or 6 membered fully saturated or partially saturated monocyclic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, linked by a ring carbon atom or a ring nitrogen atom. 4. Examples of 5-or 6-membered heterocyclic rings include azetidine, tetrahydrofuran, tetrahydropyran, pyrroline, pyrrolidine, thiazolidine, morpholine, piperidine, piperazine, dihydropyridine, dihydropyrimidine, and azepane.
The term "-SOp-R 5", when p is selected to be 0, represents an alkylthio group; p is selected as 1, and represents a sulfoxide substituted by R 5; when p is selected to be 2, R 5 is sulfonyl substituted.
The compound and pharmaceutically acceptable salts thereof can be prepared into granules, powder, capsules, tablets or oral liquid according to a conventional medicine preparation method. Can be applied to the individual in need of treatment by oral administration, intraperitoneal injection, subcutaneous injection, intravenous injection, intramuscular injection, mucosal administration and other ways according to dosage forms. The dosage of the invention is generally 1-1000 mg/kg body weight/day, and can be specifically changed according to the age, illness state and the like of the individual.
The invention has the advantages that:
The inventor carries out chemical transformation on P7C3-A20 compounds to synthesize a large class of chloropropyl carbazole compounds with brand new structures; subsequently, whether this new compound has potential protective effect was tested using a fatty liver cell model (lipotoxicity and inflammation induction effect of palmitic acid on liver cells) and a type 2 diabetes cell model (induction of insulin resistance on liver cells using sucrose with high concentration, mimicking insulin resistance of peripheral metabolic organs, which are the key causative links of type 2 diabetes). The results show that the compound has remarkable treatment effect on glycolipid metabolic diseases, has remarkable effect and has clinical application potential.
Drawings
Fig. 1: potential therapeutic effect of compound I 1 on fatty liver on cellular model. ## P <0.01PA vs. blank, P <0.01 vs. PA alone. N=8. PA, palmitic acid.
Fig. 2: potential therapeutic effect of compound I 2 on fatty liver on cellular model. ## P <0.01PA vs. blank, P <0.01 vs. PA alone. N=8. PA, palmitic acid.
Fig. 3: potential therapeutic effect of compound I 3 on fatty liver on cellular model. ## P <0.01PA vs. blank, P <0.01 vs. PA alone. N=8. PA, palmitic acid.
Fig. 4: potential therapeutic effect of compound I 4 on fatty liver on cellular model. ## P <0.01PA vs. blank, P <0.01 vs. PA alone. N=8. PA, palmitic acid.
Fig. 5: oil red O staining the picture.
Fig. 6: oil red O staining statistical bar graph.
Fig. 7: potential therapeutic effects of I 1-I4 compounds on type 2 diabetes on cellular models.
Fig. 8: effects of compounds I 1 and a20 on liver tissue triglyceride content of fatty liver animal models.
Detailed Description
The technical solution of the present invention will be clearly and completely described in conjunction with the specific embodiments, but it will be understood by those skilled in the art that the examples described below are some, but not all, examples of the present invention, and are intended to be illustrative only and should not be construed as limiting the scope of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Examples 1-5 are synthetic methods for the preparation of novel compounds. Examples 6-10 are protection (activity) tests for novel compounds.
The partial reagents and the like used in the embodiments of the present invention may be as follows:
Example 1: preparation of 1- (3-bromo-6-methanesulfonyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol (Compound I 1)
The preparation route of compound I 1 of this example is shown above, and the preparation method comprises the following steps:
a. 6g of 3, 6-dibromocarbazole was dissolved in 60mL of N, N-dimethylformamide, 1.2g of potassium hydroxide powder was added, the mixture was stirred at room temperature for 1 hour, 6.2g of epibromohydrin was added dropwise, and the mixture was reacted at room temperature for 3 hours. The reaction was diluted with 100mL of water, filtered, and the solid was collected and dried to give compound 1 (6 g, 85.7%) as a white solid.
B. Compound 1 (6 g), meta-aminoanisole (2.2 g) and bismuth chloride (2.6 g) were added to cyclohexane (120 mL) and reacted at 90℃for 2 days. The reaction solution was cooled to room temperature, ethyl acetate (200 mL) and water (200 mL) were added, the mixture was allowed to stand, the organic phase was separated, saturated brine was washed once, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give Compound 2 (1.9 g, 23.7%) as a white solid.
C. Compound 2 (500 mg), sodium methane sulfinate (151 mg), cuprous iodide (37 mg) and L-proline (23 mg) were added to dimethyl sulfoxide (10 mL), and reacted at 150 ℃ under nitrogen for 4 hours. The reaction solution was cooled to room temperature, water (40 mL) was then added, the extracts were extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give Compound I 1 (210 mg, 46%).
The compounds obtained in each step are subjected to conventional separation and purification, pure products are characterized, and structural characterization data are respectively as follows:
Calculated for compound 1：1H NMR(CDCl3)δ:8.16(d,J＝1.8Hz,2H),7.59(dd,J＝8.7,1.9Hz,2H),7.35-7.37(m,2H),4.67(dd,J＝15.9,2.7Hz,1H),4.31(dd,J＝15.9,5.1Hz,1H),3.32-3.36(m,1H),2.82-2.85(m,1H),2.51-2.53(m,1H);ESI-MS:m/z C15H11Br2NO[M+H]+: 381.9; actual measurement value: 381.9;
Calculated for compound 2：1H NMR(CDCl3)δ:8.17(d,J＝1.8Hz,2H),7.58(dd,J＝8.7,1.9Hz,2H),7.36-7.38(m,2H),7.11(t,J＝8.1Hz,1H),6.36(dd,J＝8.1,2.1Hz,1H),6.26(dd,J＝8.0,1.9Hz,1H),6.17(t,J＝2.2Hz,1H),4.38-4.45(m,3H),4.02(m,1H),3.76(s,3H),3.34-3.38(m,1H),3.20-3.24(m,1H),2.18(d,J＝3.3Hz,1H);ESI-MS:m/z C22H20Br2N2O2[M+H]+: 504.9; actual measurement 504.9;
calculated for compound I1：1H NMR(CDCl3)δ:8.66(d,J＝1.6Hz,1H),8.28(d,J＝1.8Hz,1H),8.00(dd,J＝8.7,1.8Hz,1H),7.61-7.66(m,2H),7.45(d,J＝8.7Hz,1H),7.12(t,J＝8.1Hz,1H),6.36(dd,J＝8.2,2.1Hz,1H),6.27(dd,J＝8.0,1.9Hz,1H),6.18-6.19(m,1H),4.41-4.56(m,3H),4.05-4.07(m,1H),3.77(s,3H),3.37-3.41(m,1H),3.21-3.26(m,1H),3.14(s,3H),2.35(d,J＝3.3Hz,1H);ESI-MS:m/z C23H23BrN2O4S[M+H]+: 505.1/503.1; found 505.1/503.1.
Example 2: preparation of N- (3- (3-bromo-6-methanesulfonyl-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline (Compound I 2)
The preparation route of compound I 2 of this example is shown above, and the preparation method comprises the following steps:
d. P7C3-A20 (200 mg), sodium methane sulfinate (60 mg), cuprous iodide (14.8 mg) and L-proline (8.9 mg) were added to dimethyl sulfoxide (4 mL), and reacted at 150℃under nitrogen atmosphere for 5 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give Compound I 2 (85 mg, 43.3%).
Calculated for compound I2：1H NMR(CDCl3)δ:8.63(d,J＝1.6Hz,1H),8.25(d,J＝1.7Hz,1H),7.99(dd,J＝8.7,1.7Hz,1H),7.62(dd,J＝8.7,1.8Hz,1H),7.53(d,J＝8.7Hz,1H),7.36(d,J＝8.7Hz,1H),7.11(t,J＝8.1Hz,1H),6.36(dd,J＝8.2,2.0Hz,1H),6.25(dd,J＝8.0,1.8Hz,1H),6.15-6.17(m,1H),5.04-5.18(m,1H),4.61-4.69(m,2H),3.91-4.03(m,1H),3.76(s,3H),3.28-3.53(m,2H),3.12(s,3H);ESI-MS:m/z C23H22FBrN2O3S[M+H]+: 507.1/505.1; actual measurement value: 507.1/505.1.
Example 3: preparation of N- (3- (3-bromo-6-cyano-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline (Compound I 3)
The preparation route of compound I 3 of this example is shown above, and the preparation method comprises the following steps:
e. P7C3-A20 (200 mg) and cuprous cyanide (35 mg) were added to N-methylpyrrolidone (4 mL), and reacted at 150℃for 6 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 ml×2), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give compound I 3 (14 mg, 7.8%).
Calculated for compound I3：1H NMR(CDCl3)δ:8.35(d,J＝1.0Hz,1H),8.22(d,J＝1.8Hz,1H),7.71(dd,J＝8.6,1.5Hz,1H),7.62(dd,J＝8.7,1.9Hz,1H),7.48(d,J＝8.6Hz,1H),7.35(d,J＝8.7Hz,1H),7.12(t,J＝8.1Hz,1H),6.36(dd,J＝8.1,2.1Hz,1H),6.24(dd,J＝8.1,1.9Hz,1H),6.16(m,1H),5.05-5.19(m,1H),4.60-4.68(m,2H),3.96(t,J＝6.4Hz,1H),3.76(s,3H),3.30-3.53(m,2H);ESI-MS:m/z C23H19FBrN3O[M+H]+: 452.1/454.1; found 452.1/454.1.
Example 4: preparation of 1- (3-bromo-6-methanesulfonyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol (Compound I 4)
The preparation route of compound I 4 of this example is shown above, and the preparation method comprises the following steps:
f. P7C3 (150 mg), sodium methane sulfinate (48.4 mg), cuprous iodide (12 mg) and L-proline (7.2 mg) were added to dimethyl sulfoxide (3 mL), and reacted at 150℃under nitrogen for 4 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 ml×2), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give compound I 4 (25 mg, 16.7%).
Calculated for compound I4：1H NMR(MeOD)δ:8.68(d,J＝1.5Hz,1H),8.34(d,J＝1.6Hz,1H),7.94(dd,J＝8.7,1.8Hz,1H),7.71(d,J＝8.8Hz,1H),7.50-7.57(m,2H),7.09-7.13(m,2H),6.63-6.66(m,3H),4.56-4.60(m,1H),4.41-4.46(m,1H),4.24-4.30(m,1H),3.27-3.28(m,1H),3.22-3.27(m,1H),3.16(s,3H).;ESI-MS:m/z C22H21BrN2O3S[M+H]+: 475.1/473.1; actual measurement 475.1/473.1.
Example 5: preparation of 1- (3-bromo-6-cyano-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol (Compound I 5)
The preparation route of compound I 5 of this example is shown above, and the preparation method comprises the following steps:
g. P7C3 (150 mg) and cuprous cyanide (28.3 mg) were added to N-methylpyrrolidone (3 mL), and reacted at 150℃for 5 hours under nitrogen. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 ml×3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give compound I 5 (25 mg, 18.9%).
Calculated for compound I5：1H NMR(MeOD)δ:8.50(s,1H),8.33(d,J＝1.6Hz,1H),7.67(m,2H),7.49-7.57(m,2H),7.12(t,J＝7.9Hz,2H),6.64-6.67(m,3H),4.55-4.61(m,1H),4.39-4.45(m,1H),4.24-4.29(m,1H),3.27-3.28(m,1H),3.18-3.23(m,1H);ESI-MS:m/z C22H18BrN3O[M+H]+: 420.1/422.1; found 420.1/422.1.
Example 6: potential therapeutic effects of I 1-I4 Compounds on fatty liver on cellular models
We set up a cell fatty liver model on cultured HepG2 hepatocytes using Palmitic Acid (PA) induced hepatocytes. Cells were treated with 0.3mM PA and I 1-I4 compounds (concentrations 0.1, 1, 10. Mu. Mol/L) for 48h and the extent of cell damage was determined by measuring the level of the lipid oxidative stress marker malondialdehyde (Malondialdehyde, MDA). In addition, the degree of accumulation of lipids in cells was also determined using oil red O staining, as follows: after 48h of treatment with PA (0.3 mM) and I 1-I4 compounds (total of 5, 1. Mu. Mol/L), the cells were stained with oil red O, indicating more lipid deposition as the red area increased.
Cell damage index 1: lipid oxidative stress marker-malondialdehyde (Malondialdehyde, MDA)
(1) The therapeutic effect of the compound I 1 is shown in figure 1, and 0.1, 1 and 10 mu M of the compound I 1 has obvious inhibition effect on lipid oxidative stress induced by PA on liver cells.
(2) The therapeutic effect of compound I 2 is shown in fig. 2, and 10 μm of compound I 3 has a significant inhibitory effect on lipid oxidative stress induced by PA on hepatocytes, and is not statistically significant at the lower two concentrations.
(3) The therapeutic effect of compound I 3 as shown in figure 3, 10 μm of compound I 3 has a significant inhibitory effect on lipid oxidative stress induced by PA on hepatocytes, and has a certain effect at lower two concentrations, but is not statistically significant.
(4) The therapeutic effect of compound I 4 as shown in fig. 4, 10 μm of compound I 4 has a significant inhibitory effect on lipid oxidative stress induced by PA on hepatocytes, and has a certain effect at lower two concentrations, but is not statistically significant.
Taken together: compound I 1-4 was effective, and compound I 1 was most effective.
Cell damage index 2: oil red O staining (lipid deposition amount)
Representative pictures of oil red O staining are shown in fig. 5, and statistical results are shown in fig. 6. The presence of a much more red color in the PA-treated group compared to the control group indicates that intracellular lipid deposition occurred after PA treatment. The red areas of the PA treatment group, the compound I 1 treatment group, the PA treatment group, the compound I 3 treatment group and the PA treatment group, the compound I 4 treatment group are obviously reduced, which indicates that the compound I 1、I3、I4 has obvious inhibition effect on intracellular lipid deposition caused by PA on liver cells. Compound I 2 has a therapeutic effect at a concentration of 1 μm, but is less potent than I 1、I3、I4.
Example 7 potential therapeutic Effect of I 1-I4 Compounds on type 2 diabetes on cell models
High concentration glucose induces insulin resistance model on hepatocytes: glucose (Shanghai Ind Co., ltd.) and dexamethasone (American Sigma Co., ltd., cat. No. D4902) were dissolved in the culture medium of HepG2 liver cell strain, and the culture medium was sterilized by filtration so that the final concentration of glucose in the culture medium reached 60mM, and the final concentration of dexamethasone reached 1. Mu.M, and the cultured cells were cultured for 48 hours in total, thereby successfully preparing a type 2 diabetes model for simulating insulin resistance phenomenon of peripheral metabolic tissues.
Subsequently, we used compound I 1、I2、I3、I4 or solvent control (0.1% final concentration of dimethylsulfoxide DMSO) on cells for a total of 8 hours, then transferred into normal glucose concentration (25 mM) medium without phenol red, serum, stimulated with insulin for 4 hours with 0.1 μm stimulation, then the medium was decanted, and the glucose level of the medium was measured using the glucose assay kit (cat No. F006-1-1) of the nanjing company to determine its consumption, indirectly determining insulin sensitivity, and thus preliminarily evaluating whether compound I 1、I2、I3、I4 had a potential therapeutic effect on type 2 diabetes.
The results are shown in FIG. 7. Compared with the cells in the control group, the concentration of glucose in the culture medium of the insulin resistance model is obviously reduced, which means that the cells still cannot effectively absorb glucose under the condition of insulin stimulation. The compound I 1、I2、I3、I4 has obvious inhibition effect on the insulin resistance. This suggests that compound I 1、I2、I3、I4 has a certain antagonistic effect on type 2 diabetes.
Example 8: potential therapeutic effect of I 1 compound on fatty liver in animal model and comparison with Compound A20
We induced an animal fatty liver model on C57 normal mice on a 60% fat-powered high fat diet for 4 months, and then tested the therapeutic effect of compound I 1, compound a20 on the whole animal disease model. Specific administration information: the dosage is 20mg/kg, and the medicine is administrated by stomach irrigation once a day for 2 weeks.
The results are shown in FIG. 8. Compared with the control group, the triglyceride content of liver tissues of the compound I 1 and the compound A20 administration groups is obviously reduced, which proves that the 2 compounds can effectively reverse liver cell lipid deposition caused by high-fat diet. Moreover, compound I 1 has a stronger effect than compound a20.
Compound I 1 and compound a20 have no obvious effect on lowering cholesterol levels in liver tissues, and may be associated with a short administration time.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and additions may be made to those skilled in the art without departing from the method of the present invention, which modifications and additions are also to be considered as within the scope of the present invention.

Claims (3)

1. A carbazole compound characterized in that: the structural general formula is shown in formula (I):
The carbazole compound is selected from the group consisting of:
1- (3-bromo-6-methanesulfonyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
1- (3-bromo-6-methanesulfonyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
N- (3- (3-bromo-6-cyano-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline.
2. The pharmaceutically acceptable salt of the carbazole compound as claimed in claim 1, characterized in that: the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt; the inorganic acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid or nitric acid; the organic acid comprises acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-toluenesulfonic acid, salicylic acid or oxalic acid.
3. The use of a carbazole compound as claimed in claim 1 or a pharmaceutically acceptable salt of a carbazole compound as claimed in claim 2 for the preparation of a medicament for the treatment of glycolipid metabolic diseases and complications thereof, characterized in that the glycolipid metabolic diseases and complications thereof are fatty liver, type 2 diabetes, hyperlipidemia, obesity or arteriosclerotic cardiovascular and cerebrovascular diseases.
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CN108619137A (en) * 2018-07-10 2018-10-09 上海市第十人民医院 A kind of application of carbazole compound in preparing the drug or health food for the treatment of metabolic disease and its complication
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CN108619137A (en) * 2018-07-10 2018-10-09 上海市第十人民医院 A kind of application of carbazole compound in preparing the drug or health food for the treatment of metabolic disease and its complication
CN109627205A (en) * 2019-01-11 2019-04-16 贵州大学 The preparation method and applications of a kind of carbazyl Isopropanolamine derivatives

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